Neurons are composed of a cell body and two terminal processes: the axon at one end and a branched dendritic tree at the other. These processes are crucial for the ability of one neuron to respond to another and pass on electrochemical signals through synapses. Neuronal activity is very important in driving dendrite outgrowth, but the precise mechanisms involved are not well understood. Because neuronal activity results in increased intracellular Ca2+ concentrations, possible roles for members of the family of Ca2+/calmodulin (CaM)-dependent protein kinases (CaMKs) in translating this rise in Ca2+ into signals driving dendrite outgrowth have been investigated. Takemoto-Kimura et al. examined the role of the CaMKI family member, CLICKIII (also known as CaMKIγ and CL3). From initial studies on wild-type and mutated forms of CL3 in transfected COS-7 cells cultured in medium containing radiolabeled lipid precursors, the authors demonstrated that CL3 undergoes sequential lipid modifications of its C-terminal tail. CL3 was first prenylated, which was responsible for anchoring CL3 to the plasma membrane [as demonstrated by visualization of a green fluorescent protein (GFP)-tagged form of CL3], and then palmitoylated at specific Cys residues. Palmitoylation of a kinase-deficient mutant of CL3 (which was prenylated normally) was greatly impaired compared with that of wild-type CL3, suggesting that kinase activity induced a conformational change that was necessary for this lipid modification. Lipid fractionation experiments performed on cultured cortical neurons that were transfected with GFP-tagged CL3 demonstrated that prenylated, palmitoylated CL3 was predominantly associated with lipid raft microdomains in the plasma membrane, and fluorescence microscopy revealed that the majority of the lipid raft-localized CL3 was found in the proximal dendrites. Further studies in neurons that were removed from day 19 embryonic rats, transfected with CL3 constructs, and then cultured for 48 hours revealed that total dendrite length was enhanced by overexpression of wild-type but not kinase-deficient CL3. Knockdown of CL3 in cultured neurons by short hairpin RNA (shRNA) techniques resulted in fewer and shorter dendrites compared with control neurons. Brain-derived neurotrophic factor (BDNF) activates neurons by stimulating intracellular Ca2+, resulting in dendrite outgrowth. The authors found that siRNA-mediated knockdown of CL3 blocked BDNF-mediated dendrite formation in cultured cortical neurons. Finally, lipid raft-localized CL3 in dendrites activated the Rho GTPase family member Rac, leading to rearrangement of the actin cytoskeleton of the growing dendrite. Together these data suggest that CL3 is a key factor in transducing Ca2+ signals stimulated by extracellular factors into lipid-raft localized signals responsible for dendrite outgrowth.